| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T23714 | ||||
| Target Name | B2 bradykinin receptor | ||||
| Target Type | Successful |
||||
| Drug Potency against Target | Labradimil | Drug Info | IC50 = 10 nM | [552500] | |
| (D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Aoc-Arg | Drug Info | Ki = 0.176 nM | [529475] | ||
| (D)Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(d)Phe-Phe-Arg | Drug Info | Ki = 26.8 nM | [529475] | ||
| (D)Arg-Arg-Pro-Hyp-Gly-Thi-Cys-(D)Phe-Phe-Cys-Arg | Drug Info | Ki = 876 nM | [529475] | ||
| H-DArg-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH(JMV1638) | Drug Info | Ki = 325 nM | [525817] | ||
| (D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Tic-Arg | Drug Info | Ki = 0.381 nM | [529475] | ||
| BRADYKININ | Drug Info | Ki = 0.11 nM | [525817] | ||
| H-Lys-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-OH(JMV1669) | Drug Info | Ki = 0.4 nM | [525817] | ||
| H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-OH(JMV1431) | Drug Info | Ki = 4.4 nM | [525817] | ||
| NPC-567 | Drug Info | Ki = 20 nM | [529789] | ||
| Icatibant | Drug Info | IC50 = 1~5 nM | [552857] | ||
| H-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH(JMV1645) | Drug Info | Ki = 9.2 nM | [525817] | ||
| FR-173657 | Drug Info | IC50 = 1.4 nM | [530225] | ||
| Action against Disease Model | Icatibant | ALX-0081 selectively targets platelet adhesion under conditions of arterial flow. Platelet adhesion was completely inhibited upon spiking of ~0.4 |?g/mL ALX-0081. ALX-0081 completely blocks ex vivo platelet adhesion in blood samples of patients undergoing a PCI. The effective ALX-0081 dose, ie the concentration of ALX-0081 resulting in less than 3% surface coverage, ranged from 0.2 |?g/mL to 0.8 |?g/mL and was correlated to the VWF levels in the patients???plasma. In all animals treated with ALX-0081 (n = 8), a strong antithrombotic effect was obtained | [553101] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Isolated cell shortening measurements showed significant reduction in B(2)R knockout (B(2)R(-/-)) left ventricular cardiac myocytes' shortening. Whole-cell recordings were used to study the electrophysiological aspects of the left ventricular B(2)R(-/-) cardiomyocytes. Results showed: 1) action potential lengthening; 2) unchanged inwardly rectifying K(+) current; 3) reduced transient outward K(+) (I(to)) and L-type Ca(2+) current densities; 5) changes in kinetic properties related to I(to) and I(Ca,L). In addition, transient sarcoplasmic reticul uM (SR) Ca(2+) release was found to be smaller in B(2)R(-/-) cardiomyocytes. Importantly, evidence is provided that NO constitutive production is, at least in part, responsible for the reported electrophysiological modifications observed in cardiomyocytes from B(2)R(-/-) mice. Surprisingly, NO is not involved in the SR Ca(2+) release reduction as demonstrated in the present study. | [552500] | |||
| References | |||||
| Ref 552500 | International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev. 2005 Mar;57(1):27-77. | ||||
| Ref 529475 | J Med Chem. 1991 Mar;34(3):1230-3.Design and conformational analysis of several highly potent bradykinin receptor antagonists. | ||||
| Ref 529475 | J Med Chem. 1991 Mar;34(3):1230-3.Design and conformational analysis of several highly potent bradykinin receptor antagonists. | ||||
| Ref 529475 | J Med Chem. 1991 Mar;34(3):1230-3.Design and conformational analysis of several highly potent bradykinin receptor antagonists. | ||||
| Ref 525817 | J Med Chem. 2000 Jun 15;43(12):2382-6.Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists. | ||||
| Ref 553101 | Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs. Blood. 2011 Jul 21;118(3):757-65. doi: 10.1182/blood-2010-11-317859. Epub 2011 May 16. | ||||
| Ref 529475 | J Med Chem. 1991 Mar;34(3):1230-3.Design and conformational analysis of several highly potent bradykinin receptor antagonists. | ||||
| Ref 525817 | J Med Chem. 2000 Jun 15;43(12):2382-6.Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists. | ||||
| Ref 525817 | J Med Chem. 2000 Jun 15;43(12):2382-6.Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists. | ||||
| Ref 525817 | J Med Chem. 2000 Jun 15;43(12):2382-6.Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists. | ||||
| Ref 529789 | J Med Chem. 2008 Nov 27;51(22):7094-8.cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia. | ||||
| Ref 552857 | Therapeutic potential of icatibant (HOE-140, JE-049). Expert Opin Pharmacother. 2008 Sep;9(13):2383-90. doi: 10.1517/14656566.9.13.2383 . | ||||
| Ref 525817 | J Med Chem. 2000 Jun 15;43(12):2382-6.Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists. | ||||
| Ref 530225 | J Med Chem. 2009 Jul 23;52(14):4370-9.Novel small molecule bradykinin B2 receptor antagonists. | ||||
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